Constipation refers to a condition having decrease in stool frequency and stool output and involving pain or difficulty in fecal excretion. The frequency of constipation is presumably increasing due to change in diet, inadequate exercise, stressful social life due to many time restrictions, and aging society.
Ingested food is digested in the stomach and the small intestine, and the nutrients are mainly absorbed in the small intestine. Then, undigested bowel contents are sent from the small intestine to the large intestine. In the large intestine, the contents are solidified while water is absorbed, and the resultant is moved toward the anus by peristalsis to reach the sigmoid colon so that feces are retained. Upon entrance of the retained feces into the rectum by a contraction motion called mass peristalsis, the rectal walls expand. This stimulus is transferred to the spinal defecation center, resulting in defecation reflex to cause anal sphincter laxity and rectal contraction. At the same time therewith, the urge to defecate is recognized by the cerebrum, and the abdominal pressure is voluntarily increased to defecate. However, constipation occurs when the autonomic function, motor function, or defecation reflex function of the lower gastrointestinal tract is decreased due to aging, change in diet, or inadequate exercise, etc., or when excessive water absorption, reduced bowel fluid secretion, etc., in the intestinal tract is induced.
A large number of constipation patients often perform self-care treatment with OTC drugs, folk medicine, or the like, because constipation, albeit with discomfort, does not cause serious problems to daily life. However, constipation incurs reduction in QOL as well as generalized illness. In the case where constipation arises as a partial symptom of a systemic disease, the importance of the treatment thereof is pointed out.
Constipation is divided into organic constipation and functional constipation according to a cause thereof. The organic constipation is constipation that occurs due to the obstruction of the gastrointestinal tract attributed to colonic polyps, colorectal cancer, or the like. On the other hand, the functional constipation is classified into drug-induced constipation, symptomatic constipation, and chronic idiopathic constipation. The drug-induced constipation is constipation that is caused by a drug, such as opioid, which decreases bowel motility. The symptomatic constipation is constipation that occurs secondary due to a disease other than gastrointestinal disease. The chronic idiopathic constipation is constipation that occurs most frequently among the functional constipation cases. The chronic idiopathic constipation occurs due to stress or change in eating environment.
Irritable bowel syndrome with constipation (IBS-C) is constipation having persistent digestive symptoms composed mainly of abdominal pain or abdominal discomfort and abnormal bowel movements without organic change in gastrointestinal tract. Some of functional constipation patients are also diagnosed with IBS-C.
Examples of drugs for constipation include: osmotic laxatives classified into saline laxatives such as magnesium oxide or sugar laxatives such as lactulose; bulk-forming laxatives such as calcium polycarbophil; stimulant laxatives such as sennoside and sodium picosulfate; and emollient laxatives such as dioctyl sodium sulfosuccinate. A serotonin 4 (5-HT4) receptor agonist such as prucalopride, a type-2 chloride channel (ClC-2) agonist such as lubiprostone, or the like is also used.
For the medication of constipation, a saline laxative or a bulk-forming laxative is first used. The saline laxative magnesium oxide requires attention to hypermagnesemia in aged people or renal damage or the like. The bulk-forming laxative calcium polycarbophil acts mildly and requires time for exerting its effects. If these drugs are insufficient, a stimulant laxative is used. However, the stimulant laxative becomes addictive by long-term usage and causes atrophy of the enteric plexus and deterioration in the laxity of the large intestine, although this laxative acts on the enteric plexus and enhances peristalsis. Its use is limited to the minimum amount for the minimum period.
Lubiprostone, which has been approved in recent years, manifests nausea or vomiting as an adverse effect. This drug also requires careful administration for patients with severe renal dysfunction.
Thus, the existing therapeutic drugs for constipation are not yet perfect in terms of safety and efficacy, and all of the drugs are not highly satisfactory according to the reports (Non Patent Literatures 1 and 2). There is a demand for the development of a safer and more effective therapeutic drug for constipation. Such a drug is considered to be beneficial for many patients with chronic constipation.
Digestive juice secreted into the gastrointestinal tract is rich in sodium. This sodium is reabsorbed by the gastrointestinal tract so that the homeostasis of sodium in the body is maintained. Specifically, the gastrointestinal tract absorbs 9 L of body fluids and approximately 800 mmol of sodium in which 7.5 L of body fluids and 650 mmol of sodium are derived from the digestive juice, and the remaining 1.5 L of body fluids and 150 mmol of sodium are orally derived (Non Patent Literature 3). The gastrointestinal tract absorbs almost the whole amount of sodium, and the amount of sodium excreted into feces is approximately 5 mmol.
A principal mechanism for this sodium reabsorption is electroneutral transport and electrogenic transport (Non Patent Literature 4). The electroneutral transport is mainly mediated by NHE3 expressed in the small intestine and the proximal colon. For example, about half of the sodium absorption in the jejunum is reportedly derived from NHE3 (Non Patent Literature 5). The electrogenic transport is mediated by the epithelial sodium channel ENac in the distal colon.
A substance inhibiting the NHE3 activity in the intestinal tract (hereinafter, referred to as a NHE3-inhibiting substance) allows sodium to be retained in the intestinal tract by suppressing intestinal sodium absorption. The retained sodium draws out water by osmotic pressure and therefore softens intestinal contents. Therefore, the NHE3-inhibiting substance is considered to be useful as a therapeutic drug for chronic constipation, IBS-C, or drug-induced constipation (Non Patent Literatures 6 and 7).
The NHE3-inhibiting substance also allows sodium to be excreted into feces by suppressing intestinal sodium absorption. Therefore, the NHE3-inhibiting substance is considered to be also useful as a drug that mimics salt restriction.
An antihypertensive drug such as an angiotensin receptor antagonist or an angiotensin-converting enzyme inhibitor is used as an existing therapeutic drug for hypertension or therapeutic drug for nephropathy. However, the effects of these drugs are not sufficient. Although dietary salt restriction is known to be beneficial for the prevention and treatment of these diseases, it is difficult to continuously comply with salt restriction in modern life. Meanwhile, the NHE3-inhibiting substance that mimics salt restriction has been reported to decrease blood pressure in rats and further to decrease blood pressure more strongly by combined use with an angiotensin-converting enzyme inhibitor (Non Patent Literature 6). Therefore, the NHE3-inhibiting substance is considered to exert therapeutic effects in monotherapy and combination therapy with an existing antihypertensive drug.
Here, renal failure patients with severe renal dysfunctions cannot sufficiently excrete redundant sodium and body fluids into urine. Furthermore, the efficacy of a diuretic also disappears. Therefore, the patients must receive hemodialysis several times a week. Body weight gain and blood pressure elevation occur due to body fluid retention between dialysis sessions, and blood pressure reduction occurs through amelioration in body fluid retention by dialysis operation. Such blood pressure elevation and reduction caused by repeated body fluid retention and dialytic water removal adversely affect the cardiac functions of the renal failure patients and cause the risk of developing heart disease and poorer prognosis. Therefore, strict salt restriction and water deprivation are demanded on the renal failure patients in order to reduce variations in blood pressure. However, it is difficult to comply with this regimen due to its stringency. The NHE3-inhibiting substance has been reported to enhance sodium excretion into feces in rats, to inhibit body fluid retention, and to prevent cardiomegaly (Non Patent Literature 7).
Therefore, the NHE3-inhibiting substance is considered to be also useful as a drug for reducing the risk of developing heart disease in renal failure patients.
Meanwhile, a certain kind of NHE3-inhibiting substance has been reported not only to inhibit intestinal sodium absorption but to inhibit phosphorus absorption and to enhance phosphorus excretion into feces (Patent Literature 24 and Non Patent Literature 8). A certain kind of NHE3-inhibiting substance has been further reported to lower phosphorus concentration in blood by administration to renal failure rats.
Phosphorus metabolism is maintained by two main effects, absorption and excretion in the small intestine and the kidney. Approximately 1.2 g/day of phosphorus is ingested, ⅓ (approximately 0.4 g) of which is excreted into feces and the remaining ⅔ (approximately 0.8 g) of which is absorbed (Non Patent Literature 9). Further, approximately 0.8 g/day of phosphorus is excreted into urine. Digestive juice also contains phosphorus, which is excreted into feces. In the body as well, phosphorus is held in equilibrium between the bone and blood.
Here, renal failure patients with severe renal dysfunctions cannot excrete approximately 0.8 g/day of phosphorus. Therefore, their phosphorus concentrations in blood are elevated to cause hyperphosphatemia. In the hyperphosphatemia, abnormal functions of the bone or the parathyroid gland occur, causing osteoporosis or hyperparathyroidism. Furthermore, phosphorus deposits in a blood vessel, together with calcium, to calcify the blood vessel. Therefore, the risk of developing cardiovascular disease is increased.
The guideline of the Japanese Society for Dialysis Therapy, “Clinical Practice Guideline for the Management of Chronic Kidney Disease-Mineral and Bone Disorder”, has reported that deranged mineral metabolism in chronic kidney disease largely influences not only abnormalities in the bone or the parathyroid gland but life prognosis via vascular calcification or the like, and has proposed such a combined disorder as chronic kidney disease-mineral and bone disorder (hereinafter, also referred to as CKD-MBD) (Non Patent Literature 10). The CKD-MBD guideline points out that, particularly, hyperphosphatemia causes abnormal functions of the bone or the parathyroid gland, aggravates vascular calcification, increases the risk of developing osteoporosis or cardiovascular disease, and largely influences life prognosis. The guideline further recommends managing hyperphosphatemia by remedy as a priority.
For renal failure patients, phosphorus in blood is removed by dialysis. However, it is impossible to keep phosphorus concentration in blood in a normal range by dialysis alone. Therefore, a phosphate binder serving as a therapeutic drug for hyperphosphatemia is used as the second-best approach. The phosphate binder is a drug that enhances phosphorus excretion by binding to phosphorus in the intestinal tract and moving in this bound state into feces. Such a drug, albeit having a reliable effect of lowering phosphorus concentration in blood, has large medication burdens with a daily dose of several grams. The medication burdens significantly impair adherence for dialysis patients who are originally forced to restrict water intake and need to take a large number of tablets. The phosphate binder is classified into metal-containing type and polymeric phosphate binders, each of which presents problems. The metal-containing phosphate binder presents concerns about long-term safety due to metal loading. Also, the polymeric phosphate binder swells in the intestinal tract and therefore frequently causes gastrointestinal symptoms such as constipation or abdominal distention.
Therefore, a drug improved in terms of safety and convenience and having good adherence is desired as a novel therapeutic drug for hyperphosphatemia.
The NHE3-inhibiting substance neither contains a metal nor is a polymer and is therefore free from the adverse reactions specific for the phosphate binder described above. Also, the NHE3-inhibiting substance can probably reduce a dose as compared with the phosphate binder. Therefore, the NHE3-inhibiting substance is considered to be useful as a therapeutic drug for hyperphosphatemia improved in terms of safety and convenience and having good adherence. Furthermore, the NHE3-inhibiting substance that can be used for a long period is considered to be useful as a drug ameliorating CKD-MBD.
Water restriction is demanded on renal failure patients so as not to aggravate body fluid retention. Therefore, the water content in the intestinal tract is decreased. The renal failure patients also have the risk of hyperkalemia. Thus, restriction of vegetable intake is imposed thereon in order to restrict potassium intake. Due to the restriction of the water and vegetable intake, the renal failure patients develop constipation with high frequency. The NHE3-inhibiting substance is considered to also have an ameliorating effect on constipation specific for renal failure patients.
Thus, the NHE3-inhibiting substance serves as a drug capable of treating hyperphosphatemia and CKD-MBD in renal failure patients, a drug capable of mitigating body fluid retention, and a drug capable of ameliorating even constipation in renal failure patients, and is expected as a very useful drug that comprehensively improves QOL of renal failure patients.
Body fluid retention also occurs in heart failure patients. This body fluid retention further aggravates cardiac functions. In general, a diuretic is used in the treatment of heart failure. However, the diuretic may exhibit attenuated efficacy for patients with reduced renal functions and cause potassium abnormalities. The NHE3-inhibiting substance can allow body fluids to be excreted into feces, regardless of renal functions. Therefore, the NHE3-inhibiting substance is considered to be useful as a novel therapeutic drug for heart failure.
In addition, body fluid retention also occurs in liver cirrhosis patients. Furthermore, for example, a PPAR agonist, which is useful in the treatment of type 2 diabetes mellitus, also causes drug-induced body fluid retention. The NHE3-inhibiting substance is considered to be also able to mitigate such body fluid retention.
Acylguanidine derivatives (Patent Literature 1), amidine derivatives (Patent Literatures 2 and 3), guanidine derivatives (Patent Literatures 4 to 6), tetrahydroisoquinoline derivatives (Patent Literatures 7 to 14), 2-aminoimidazolidine or 2-aminoimidazole derivatives (Patent Literatures 15 to 19), aminodihydroisoquinoline derivatives (Patent Literatures 20 and 21), aminoindane derivatives (Patent Literatures 22 and 23), and the like have been reported as compounds inhibiting NHE3. Nonetheless, no compound having the structure of the present invention has been disclosed.
A certain kind of NHE3-inhibiting compound has been reported to have a phosphorus absorption inhibitory effect. Nonetheless, this effect has not been reported as to a compound having the structure of the present invention (Patent Literature 24 and Non Patent Literature 8).